One of the major public health issues in the United States today is the high prevalence of myocardial infarction in previously asymptomatic patients. The dominant cause is acute rupture of vulnerable atherosclerotic plaques, but no test is currently available to non-invasively identify vulnerable plaques during the asymptomatic stage. The quantum leap needed to address this profound health issue and the goal of this proposal is to develop a non-invasive technique that detects vulnerable plaques prior to rupture. Extravasation of erythrocytes and intra-plaque hemorrhage are considered critical factors in the transition of a plaque from the stable to unstable state. As a consequence, iron, a main component of red blood cells, accumulates in the artery wall and its presence indicates impending rupture. A major challenge in using iron as an imaging marker of vulnerable plaque is the concurrent presence of calcium. Unlike iron, coronary calcifications represent overall plaque burden rather than vulnerability. The great problem resulting from the co-localization of iron and calcium in individual plaques is that they are indistinguishable on both magnetic resonance imaging and x-ray computed tomography (CT), the two most accepted modalities for non-invasive imaging of coronary arteries. To solve this problem, we have recently applied dual-energy CT, which subtracts images acquired with substantially different energy spectra to discriminate materials that appear similar on conventional CT, such as iron and calcium. Based on our successful preliminary work, our central hypothesis is, therefore, that dual-energy CT can directly detect vulnerable plaques in vivo by virtue of iron accumulation in the artery wall. Our objective during Phase I of this Quantum Program is to detect iron as a marker of vulnerable plaques despite the presence of calcium. The specific aims are (1): To develop an imaging technique that can detect iron and discriminate iron from calcium. Our working hypothesis is that CT images simultaneously acquired using a new dual-source CT system at two different x-ray tube potentials can be combined to unequivocally differentiate iron from calcium. We will use mixtures of iron and calcium solutions and sub-mm particles, as well as explanted specimens of diseased vessels. Aim (2) is designed to measure intramural iron in vulnerable plaques of arterial specimens and in vivo. a) Using high resolution, dual-energy microscopic CT (micro-CT), we will quantify the prevalence, concentration, and distribution of iron deposits in vulnerable plaques. b) Finally, we will validate our dual-energy techniques in vivo using a diabetic pig model that develops unstable atherosclerotic lesions similar to patients. Histological techniques will be used to classify plaque stages. In Phase II, we will build a new generation of CT technology with the performance characteristics necessary to accurately detect hemorrhagic plaque in humans. The significance of this proposal is that by detecting and treating pre-symptomatic vulnerable plaques before they rupture, the premature death, loss of productivity, hospitalization and treatment cost to society can be markedly reduced.